Metabolism of diphenylhydantoin by rat liver microsomes—i

Kutt, Henn; Verebely, Karl

doi:10.1016/0006-2952(70)90230-3

Cited by 55 publications

(18 citation statements)

References 12 publications

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“…Upon consideration of the primary metabolic pathways of the drugs affected and the enzymes catalyzing them, many of these drug-drug interactions appear to be attributable to pharmacokinetic changes that can be understood in terms of alterations of multiple hepatic drug metabolic pathways catalyzed by the cytochrome P450 (CYP450) system (2). In fact, the ability of INH to inhibit the hepatic CYP450 system in vitro in rat liver microsomes has been described (25,34). In animals (6), it has been shown that INH effectively inhibits para-hydroxylation of phenytoin in vivo.…”

mentioning

confidence: 99%

Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

Desta

Soukhova

Flockhart

2001

Antimicrob Agents Chemother

156

122

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Isoniazid (INH), introduced in the 1950s, continues to be one of the most safe and cost-effective agents used to treat tuberculosis (9). Because of the increasing incidence of tuberculosis that has resulted from the coepidemic of human immunodeficiency virus infection (32), the use of INH in the prevention (9, 17) and treatment (9) of tuberculosis is on the rise. INH is often given chronically to critically ill patients who are on multiple medications to treat tuberculosis and AIDS-related mycobacterial disease (18, 45), raising the potential for adverse drug-drug interactions.In humans, INH has been found to decrease the clearance of several drugs, including phenytoin (see, e.g., references 3, 24, and 30), carbamazepine (54, 58, 59), diazepam (36), triazolam (37), vincristine (7), primidone (48), and acetaminophen (10, 35), sufficiently to require a reduction of the dose or discontinuation of INH. Upon consideration of the primary metabolic pathways of the drugs affected and the enzymes catalyzing them, many of these drug-drug interactions appear to be attributable to pharmacokinetic changes that can be understood in terms of alterations of multiple hepatic drug metabolic pathways catalyzed by the cytochrome P450 (CYP450) system (2). In fact, the ability of INH to inhibit the hepatic CYP450 system in vitro in rat liver microsomes has been described (25,34). In animals (6), it has been shown that INH effectively inhibits para-hydroxylation of phenytoin in vivo. Despite the strong link between INH drug interactions and inhibition of the CYP450 system and despite its widespread use for more than 4 decades, our knowledge is incomplete with respect to which specific CYP450 isoforms are inhibited, making prediction of drug interactions with INH difficult. The only isoform that has been studied in detail in human and animal models is CYP2E1, for which INH has been reported to have a biphasic effect (induction and inhibition) (8). This property of INH may explain the increased risk of hepatotoxicity of coadministered compounds (e.g., ethanol and acetaminophen) (10,33,35), but it is unlikely to explain the clinically documented interactions with other drugs, as most of them appear to be catalyzed by CYP isoforms other than CYP2E1 (e.g., phenytoin by CYP2C9 and CYP2C19 and carbamazepine by CYP3A and CYP2C8 [2,28]).In order to enable physicians to improve predictions about which drugs might interact with INH, the present study was undertaken to evaluate the inhibitory potency of INH on six common human drug-metabolizing CYP450 isoforms in vitro.

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mentioning

confidence: 99%

Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

Desta

Soukhova

Flockhart

2001

Antimicrob Agents Chemother

156

122

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“…The parameters calculated for our patients may be compared with a 'Km' of 26.8 iumol/1 and a 'Vmax' of 1 ytmol/l/hour determined by Gerber and Wagner (1972) for a single subject and with the mean values of a 'Km' of 15.1 ptmol/l and 'Vmax' 1.36 pmol/l/hour determined by Mawer et al (1974) from 15 patients. Kutt and Verebely (1970) found that diazepam inhibited phenytoin metabolism by rat liver microsomes in vitro. With 10-3 M diazepam 91% inhibition occurred, and 32% inhibition with 10-4 M, but the type of inhibition was undetermined.…”

Section: Discussionmentioning

confidence: 96%

“…Studies on phenytoin metabolism by rat liver microsomes in vitro by Kutt and Verebely (1970) showed the drug to be metabolised by an enzymic process obeying Michaelis-Menten kinetics, the rate-limiting step being parahydroxylation to 5-p-hydroxyphenyl-5-phenylhydantoin. Measurement of the apparent Km for this process gave a mean value of 37.3 ,tmol/l.…”

Section: Discussionmentioning

confidence: 99%

Phenytoin intoxication during concurrent diazepam therapy

Rogers

Haslam

Longstreth

et al. 1977

Journal of Neurology, Neurosurgery & Psychiatry

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Phenytoin possesses a relatively small therapeutic index, and toxicity is by no means uncommon during therapy making monitoring of plasma levels an important adjunct to clinical management (Dawson and Jamieson, 1971). This situation is further complicated by the non-linear relationship between dose and the resulting plasma concentration (Bochner et al., 1972). The apparent half-life of the drug increases as the plasma level rises, phenytoin elimination being described as dose-dependent. This type of elimination can be described as obeying Michaelis-Menten kinetics overall (Gerber and Wagner, 1972). It follows from these kinetic properties that the relationship of plasma levels to dose is non-linear, and that at higher plasma levels a small increase in dose produces a disproportionately large increase in plasma levels. The Institute for evaluation and the dose of phenytoin increased to 9 mg/kg/day which resulted in levels of 36 ,tmol/l. Diazepam was added (for spasticity) in a dose of 0.3 mg/kg/day and increased by increments of 0.1 mg/kg/day at intervals of approximately five days to 0.6 mg/kg/day. Simultaneously the phenytoin dose was increased to 12.5 mg/kg/ day. Fourteen days after the addition of diazepam and the increased dose of phenytoin the patient experienced phenytoin toxicity characterised by 890

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“…Tris-ATP and the sodium salt of 5,5-diphenylhydantoin (DPH) were obtained from Sigma Chemical Co., St. Louis, Mo. ; ['y-"P]-ATP was obtained from International Chemical and Nuclear Corp., Irvine, Calif.; and 5-(p-hydroxyphenyl) -5-phenylhydantoin (HPPH) was a generous gift from Dr. Henn Kutt (8 Microsomal (Na+ + K+) -ATPase was prepared from rat and cat brains in a procedure using NaI (9) The activation of ATPase activity by sodium ion is shown in Fig. la maximum rates are obtained at the optimal Na: K ratio.…”

Section: Methodsmentioning

confidence: 99%

“…HPPH is the main excretory product of DPH (18) and is found conjugated with glucuronic acid in the urine (19). The liver is an important site for the formation of HPPH (8). If …”

Section: Methodsmentioning

confidence: 99%

Sodium-potassium-activated adenosine triphosphatase of brain microsomes: modification of sodium inhibition by diphenylhydantoins

Siegel¹

1972

J. Clin. Invest.

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A B S T R A C T Effects of diphenylhydantoins on (Nae + K+)-ATPase activity in rat and cat brain microsomes were studied. 5,5-diphenylhydantoin (DPH) in concentrations of 5-20 sLg ml' produces an apparent stimulation of the rat brain (Na' + K+) -activated ATPase of 55-65% in media containing 50 mm Na+, 0.15 mm K+, 3 mM Mg++, and 3 mm ATP. No effects are found on the Mg-ATPase. At constant K+ levels of 0.05 mmole/liter and 0.15 mmole/liter, increasing the Na+ concentration activates the enzyme similarly with and without DPH. However, Nat concentrations greater than 5 mmoles/ liter and 10 mmoles/liter, respectively, which are inhibitory in these low Ke media, produce less inhibition in the presence of DPH. In media containing 10 mm Nat, the K+ activation, on the other hand, is potentiated by DPH. In preparations from cat brain qualitatively similar results are obtained. No effect of DPH is seen on the inhibition produced by high K+ in low Na' media. DPH produces an approximately constant apparent stimulation of 45% in the (Na++ K+) increments when these ions are varied simultaneously at a fixed ratio of 150 Na+: 1 Ki with cat brain extracts. 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH) has the same potency as DPH in reducing the Nat inhibition at high Na: K ratios. The hydantoins appear to act by decreasing the Na+ inhibition that occurs at high Na: K ratios.

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Metabolism of diphenylhydantoin by rat liver microsomes—i

Cited by 55 publications

References 12 publications

Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

Inhibition of Cytochrome P450 (CYP450) Isoforms by Isoniazid: Potent Inhibition of CYP2C19 and CYP3A

Phenytoin intoxication during concurrent diazepam therapy

Sodium-potassium-activated adenosine triphosphatase of brain microsomes: modification of sodium inhibition by diphenylhydantoins

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